Exposure to environmental arsenicals has been linked to a number of human pathologies, include bladder and lung cancer. We hypothesize that arsenical-mediated perturbation of the epigenetic landscape is an important factor that drives malignant progression. Three integrated specific aims are described in this proposal will address this hypothesis from a gene to genome wide analysis, and from in vitro to real world settings. Aim 1 is designed to develop epigenetic targets as biomarkers of arsenical exposure. Preliminary epigenome-wide scanning studies of urine sediments from individuals with known exposure levels in their drinking water have identified candidate epigenetic biomarkers are correlated with arsenical exposure level. The utility of these candidate biomarkers will be evaluated using high sensitivity, high resolution technologies in a new cohort population. Aim 2 will determine if arsenicals produce common perturbations to the epigenomic landscape in their distinct epithelial targets. Experimental strategies of arsenical exposure that caused malignant transformation of urothelial cells will be expanded to lung epithelial model systems. Results from these experiments will help determine if there are seminal epigenetic changes that are common to epithelial malignant transformation in general, as well as the epigenetic changes that display tissue-origin specificity. Aim 3 will provide a detailed investigation of the phenotypic consequences of epigenetic gene inactivation of an arsenical target gene, G0S2, which is closely linked to the malignant transformation of urothelial cells. If our hypothesis is correct, then results from these studies will provide new insights into the mechanisms of their chronic arsenical exposure, as well as serve as a platform for inquiries into other, non-cancer, arsenic-induced human pathologies, such as diabetes and cardiovascular disease.